2-substituted amino-2h-1, 2, 4-benzothiadiazine 1, 1-dioxides



United States Patent Ice W Patented Apr. 113, 1967 SCHEME B 3,314,949 1 Z-SUBSTITUTED AMINO-2H-1,2,4-BENZO- -NH, NH: P H LTHIADIIJAZIN%1,1-DI0XHS)ES B I eter Wei pper arby and tanley C. el L N-NHR Philadelphia, Pa, assignors to American Home Prod: S0201 SONHNHR s ucts Corporation, New York, N.Y., a corporation of 01 Delaware 4 5 6 No Drawiug.7 Filed Feb. 14, 1964, Ser. No. 344,820

s. L260 243) The starting 2-(2-amino-4-chloro-5-methylphenylsul- 10 fonyl)-1-acetylhydrazide (2) (5) can be prepared according to the following general procedure which involves This invention relates to compositions of matter clastreating a 2-amino-4-chloro-S-methylphenylsulfonyl chlosified in the art of chemistry as substituted benzothiaride (1) (4) with a mixture of acetylhydrazide and diazines. triethylamine in alcohol.

The invention sought to be patented in its principal According to one procedure, the physical embodiments composition aspect resides in the concept of a composiof our concept are made by reacting an above-described tion of matter being a chemical compound having a 2-(2-amino-4-chloro-5-methylpheny1sulfonyl)-1 acetylmolecular structure in which there is attached to the hydrazide with phosgene thereby forming a Z-acetamido- 2-position of the ZH-l,2,4-benzothiadiazine 1,1-dioxide 2H-l,2,4-benzothiadiazin 3(4H)-one 1,1-dioxide (3) (6). nucleus an acetamido group or its hereinafter disclosed The reaction is usually carried out in an inert solvent equivalents. such as 1,2-dimethoxyethane and at the reflux tempera- The tangible embodiments of the principal composition ture of the reaction mass for a time sufficient to comaspect of the invention possess the inherent general plete the reaction. The proportion of the reactants may physical properties of being relatively high melting crysbe in equimolar quantities, but, preferably, a slight excess talline solids; are substantially insoluble in water and of phosgene is used. are soluble in polar solvents, such as lower aliphatic The substituted Z-aminophenylsulfonyl halides (i.e., alcohols. Examination of the compounds produced acchlorides, bromides, and fluorides) and the hydrazides cording to the hereinafter described process reveals, upon used in the above-described process are generally known spectrographic analysis, spectral data confirming the or are readily prepared by procedures known to those molecular structure hereinbefore set forth. The aforeskilled in the art. mentioned physical characteristics taken together with It will be apparent from the disclosure herein to those the nature of the starting materials and the mode of skilled in the art of organic chemistry that for the pursynthesis positively confirm the structure of the composiposes of this invention, certain of the carbon atoms of tions sought to be patented. the Z-aminophenylsulfonyl chlorides, bromides and The tangible embodiments of the principal composifluorides employed as starting materials can be subtion aspect of the invention possess the inherent applied stituted with non-interfering groups. Therefore, in the use characteristic of exerting qualitatively varying theraprocess of the invention, all 2-aminophenylsulfonyl chlopeutic effects, as evidenced by pharmacological evaluation rides, bromides and fluorides can be employed in the according to standard procedures. These tangible emprocess of making aspect of this invention to form combodiments show anti-Parkinsonian, hypotensive, and pounds which are the full equivalents of the invention muscle-relaxant effects. as particularly claimed. For example, but without limita- The manner and process of making the invention will tion, either the 3-, 4-, or the 5-position of the 2-aminonow be generally described so as to enable a person phenylsulfonyl starting compound can be substituted with skilled in the art of chemistry to make the same. an alkyl group such as methyl, ethyl, propyl, isopr-opyl The new process of the invention is illustrated scheand hexyl, a halogen atom such as a chlorine, or a matically .for a specific embodiment thereof in Scheme bromine atom, a haloalkyl group such as trifluoromethyl A, below, and more generally in Scheme B, to which and dichloromethyl, a nitro group, or an alkoxy group the numerals in parenthesis in the following description such as 'methoxy, ethoxy, propoxy, butoxy and pentoxy. refer. When the starting compounds are substituted as hereinbefore recited, it will be apparent to those skilled in the SCHEME A art that the final products formed by the process of the invention will bear, correspondingly, the same substituents. Such substituted compounds are the full equivalents of invention as particularly claimed. CH3 SO2C1 If instead of phosgene a trialkyl orthoacylate is reacted with the 2-(Z-aminophenylsulfonyl)-1-acetylhydrazide, 1 the product formed has the 2-acetamido-3-alkyl-2H- 1,2,4-benzothiadiazine 1,1-dioxide structure.

The best mode contemplated by the inventors of carryooon ing out their invention will now be set forth as follows:

0H3 SOZNHNHGOCH: Example 1.-2 acetamido 6-chl0r0-7-melhyl-2H-1,2,4-

benzothiadiazin-S (4H) -one, 1,1-di0xide 2 A. Preparation of starting materiaL To an alcoholic solution of 8.8 g. (.12 m.) of acetylhydrazide, containing 12 g. of triethylamine, add 24.0 g. (.1 m.) of 2-amino-4- chloro-S-methyl-phenylsulfonyl chloride. Reflux the N NHGOCH mixture for 1 /2 hours. Remove the alcohol at reduced CHa- \S a pressure and wash the residue with water. Recrystallize the crude material with ethanol to give 2-(2-amino-4- chloro 15 methylbenzene-sulfonyl)--1-acetylhydrazide,

3 MP. 21s-220 0.

B. Preparation of final producf.-Suspend 3.4 g. (0.01225 In.) of the above starting material in 125 cc. of dimethoxyethane. Add a solution of 1.46 g. (.0147 m.) of phosgene in the same solvent. Reflux for 6 hours. Filter any insoluble material. Concentrate the filtrate and recrystallize the residue from acetone to give Z-acetamido- 6 chloro 7 methyl 2H 1,2,4-benzothiadiazin 3(4H)-one 1,1-dioxide, M.P. 228290 (d).

The above-prepared compound was pharmacologically evaluated, as will now be described: The compound was tested for hypotensive activity by intravenous administration to anesthetized cats. The blood pressure, heart rate and respiration were recorded. Blood pressure responses to the injection of epinephrine, acetylcholine and histamine were determined before and after administration of each dose of the test compound. Nictitating membrane responses to electric-a1 stimulation were also recorded before and after administration of the compound which was injected intravenously in doses of 0.2, 2, and 20 mg./kg. approximately 30 minutes apart. The responses to the highest dose were observed for a minimum of 2 hours. The compound was considered active because it reduced blood pressure for 30 minutes.

The compound was tested as a diuretic with favorable results by the method of Lypschitz, et al., J. Pharmacol. 79:97, 1943.

The compound was tested for anti-tremorine (anti- Parkinsonian) activity with favorable results using the method of Everett et al., Science 124:79, 1956. The foregoing data indicates the effectiveness of the compound for the uses hereinbefore asserted.

The compositions constituting the invention can also be made according to the procedure hereinbefore set forth wherein substituents other than those hereinbefore enumerated are added to the benzothiadiazine nucleus. The toxicity of and the asserted actitivities of the composition so modified are not materially affected. Referring to Formula 6, Scheme B, above, such additions to the benzothiadiazine nucleus are illustrated as follows. The oxygen in the 3-position (X) 2H-1,2,4- benzothiadiazin-3(4H)ones can be converted to sulfur by heating with phosphorous pentasulfide. The 3-position (X) on the benzothiadiazines can be substituted also by a hydrogen atom and an alkyl, group as previously defined or a monocyclic aryl group such as phenyl, Z-thienyl, 3-thienyl, 2-, 3-, of 4-pyridyl, or an haloalkyl group as previously defined. Substituents in the 2- position (Scheme B, R) can be the acyl group of a carboxylic acid such as, for example but without limitation, actyl, propionyl, caproyl, benzoyl, toluyl or phenylacetyl, or a carboxamido group. Such additions to the molecular structure of the inventive concept herein described are fully equivalent to the subject matter particularly claimed.

The following example illustrates the preparation of another composition of the invention.

Example 2.2 acetamido 6 chloro-2,7-dimethyl-2H- 1,2,4-benzthiadiazin 1,1-di0xide Treat 2- 2-amino-4-chloro-S-methylphenylsulfonyl) -1- acetylhydrazide prepared as in Example I in ethanol with excess t riethyl orthoacetate. Concentrate the reaction mixture at reduced pressure and treat the oily residue with benzene. Recrystallize the crude material from a mixture of ethanol and pet. ether, M.P. 228-230 C.

It will be apparent that the compositions of our invention may be made available in unit dosage forms with the dosage adjusted for the respective activity of the particular compound by admixing them with conventional excipients, and extenders.

Accordingly, the compounds of this invention can be administered with pharmaceutically acceptable inert carriers in a wide variety of oral or parenteral unit dosage forms containing 25, 100, 250 or 500 mg. of the active ingredients, or in admixture with other active compounds.

The subject matter which the applicants regard as their where A is selected from the group of and R is selected from the group of hydrogen and lower alkyl; R is selected from the group consisting of an alkyl of less than six carbon atoms; and R and R are selected from the group consisting of hydrogen, chloro, lower alkyl, lower alkoxy, trifluoromethyl, dichloromethyl and nitro.

6. A process for preparing a compound of the formula wherein R is selected from the group consisting of hydrogen, chloro, lower alkyl, lower alkoxy, trifiuoromethyl, dichloromethyl and nitro, and R is selected from the group consisting of hydrogen, chloro, lower alkyl, lower alkoxy, trifluoromethyl, dichloromethyl and nitro, which comprises heating phosgene and a compound of the formula WNIIZ s otNHNHc 0 CH3 wherein R and R are as hereinbefore defined, in an inert organic solvent, at the reflux temperature of the mixture.

7. A process for preparing a compound of the formula N I N-NH-C O-CHa R 02 wherein R is selected from the group consisting of hydrogen, chloro, lower alkyl, lower alkoxy, trifluoromethyl, dichloromethyl and nitro; R is selected from the group consisting of hydrogen, cholor, lower alkyl, lower alkoxy, trifiuoromethyl, dichloromethyl and nitro; and R is selected from the group consisting of hydrogen and lower 5 6 alkyl; which comprises heating a compound of the in a lower alkanol medium, at the reflux temperature of formula the mixture.

(R5O3C 'R4 References Cited by the Examiner v UNITED STATES PATENTS where R is a s herelnbefore defined and R is a lower 5 3,163,644 12/1964 De Stevens et aL alkyl group, wlth a compound of the formula R3 OTHER REFERENCES NH: Hackhs Chemical Dictionary, p. 18 (1944).

10 Wertheim Textbook of Organic Chemistry, p. 763- SOr-NHNHOOCH: (1945)- NICHOLAS s. RIZZO, Primary Examiner. 

5. A COMPOUND OF THE FORMULA 